Colon cancer is the second leading cause of cancer deaths in the U.S. Despite rapid advances in human genetics, critical questions about genetic susceptibility to, and prevention of, colon cancer remain unanswered, particularly for African-Americans, who have a higher incidence and mortality rate. Our primary objective is to evaluate genetic susceptibility and environmental factors that might explain the diverging incidence and mortality trends in blacks and whites. Our secondary objective is to assess the mechanisms involved in gene-gene and gene-environment interactions and to identify high-risk (sub)populations and modifiable risk factors for colon cancer. Then it may be possible to closely tailor etiology-driven preventive strategies to the specific genetic defects conferring individual risk. We will evaluate the association between colon cancer risk and two phase II metabolic detoxification genes (GSTM]/T1), two base excision repair genes (XRCC1 and APE), a gene in double-strand break/recombination repair (XRCC3), and a nucleotide excision repair gene (XPD). The proposed study will use the existing genomic DNA samples and exposure data collected in the NCI-funded North Carolina Colon Cancer Study (NCCCS) (CA 66635). The NCCCS is a well-designed, large population-based, case-control study in a 33-county area of North Carolina with 800 newly diagnosed colon cancer cases and 800 age- and race-matched controls (50 percent blacks and 50 percent whites). The parent study is on target to complete sample and data collection by our proposed start date of January 1, 2002. The high percentage of black participants (50 percent) provides the unique opportunity to study specific risk factors in African-Americans, an understudied population at increased risk of fatal colon cancer. The large sample size provides substantial statistical power for the assessment of gene-gene and gene-exposure interactions in colon cancer risk. Our preliminary pilot data demonstrated black-white differences in genotype distributions and environmental exposures. We also observed gene-gene and gene-environment interactions in colon cancer risk. This proposed research will fill the gap between colon cancer risk assessment and prevention. Confirmation of risk profile(s) will be useful in identifying persons at high risk of colon cancer for screening and intervention. Characterization of gene-environment interactions will provideeffective strategies for dietary and lifestyle interventions, particularly in genetically susceptible (sub)populations.